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Aquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

Background IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. Case presentation We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. Conclusions Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.

Changes in the cerebral cortex of mammals during evolution have been of great interest. Ferrets, monkeys, and humans have more developed cerebral cortices compared with mice. Although the features of progenitors in the developing cortices of these animals have been intensively investigated, those of the fiber layers are still largely elusive. By taking the advantage of our in utero electroporation technique for ferrets, here we systematically investigated the cellular origins and projection patterns of axonal fibers in the developing ferret cortex. We found that ferrets have 2 fiber layers in the developing cerebral cortex, as is the case in monkeys and humans. Axonal fibers in the inner fiber layer projected contralaterally and subcortically, whereas those in the outer fiber layer sent axons to neighboring cortical areas. Furthermore, we performed similar experiments using mice and found unexpected similarities between ferrets and mice. Our results shed light on the cellular origins, the projection patterns, the developmental processes, and the evolution of fiber layers in mammalian brains.

Rationale Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a novel clinical disease entity characterized by an elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. Pathological changes are most frequently seen in the pancreas, lacrimal glands, and salivary glands, but pathological changes in the lung also exist. Linker for activation of T cell (LAT)Y136F knock-in mice show Th2-dominant immunoreactions with elevated serum IgG1 levels, corresponding to human IgG4. We have reported that LATY136F knock-in mice display several characteristic features of IgG4-RD and concluded that they constitute an appropriate model of human IgG4-RD in salivary glands, pancreas, and kidney lesions. Objectives The aim of this study is to evaluate whether lung lesions in LATY136F knock-in mice can be a model of IgG4-related lung disease. Methods Lung tissue samples from LATY136F knock-in mice (LAT) and wild-type mice (WT) were immunostained for IgG1 and obtained for pathological evaluation, and cell fractions and cytokine levels in broncho-alveolar lavage fluid (BALF) were analyzed. Results In the LAT group, IgG1-positive inflammatory cells increased starting at 4 weeks of age and peaked at 10 weeks of age. The total cell count and percentage of lymphocytes increased significantly in BALF in the LAT group compared to the WT group. In BALF, Th2-dominant cytokines and transforming growth factor-β were also increased. In the LAT group, marked inflammation around broncho-vascular bundles peaked at 10 weeks of age. After 10 weeks, fibrosis around broncho-vascular bundles and bronchiectasis were observed in LATY136F knock-in mice but not WT mice. Conclusions LATY136F knock-in mice constitute an appropriate model of lung lesions in IgG4-RD.

Background: Several studies of different cancers have revealed mutations in switch/sucrose non-fermenting (SWI/SNF) complex genes. Brahma-related gene 1 (BRG1), which is encoded by SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), is a member of this complex. SMARCA4/BRG-1-deficient non-small cell lung carcinoma (NSCLC) has been considered a subset of lung cancer that has distinct clinical, pathological, and molecular characteristics, which implies its relationship with SMARCA4/BRG1-deficient thoracic sarcoma. Case presentation: We experienced a case of SMARCA4/BRG1-deficient lung cancer in a 40-year-old female patient with a history of smoking. Magnetic resonance imaging revealed a large mass in the right lung apex with an extension to the extrapulmonary region and cerebral metastasis. Histological analysis showed poorly differentiated carcinoma with spindle cell components. She was diagnosed with NSCLC (stage IV) at that point. An EGFR mutation and ALK and ROS1 rearrangement were not detected, and then treated with chemoradiotherapy. Overall, the tumors were resistant to chemotherapy, and therefore, after 2 years, the brain tumor was excised for histological and molecular analysis. Histologically, the brain mass was an undifferentiated tumor with round cells and glandular components. The mutation in SMARCA4 in the brain specimen was identified by next-generation sequencing. Immunohistochemical examination revealed a complete loss of BRG1. SMARCA4/BRG1-deficient thoracic sarcoma had been raised as a differential diagnosis, collectively, she was diagnosed with SMARCA4/BRG1-deficient NSCLC considering for the result of positivity for cytokeratin AE1/AE3 and claudin-4, and negativity for Sal-like protein 4, CD34, and SRY-box 2 by immunohistochemical examination. Regrettably, a definitive diagnosis required approximately 2 years. She is alive with disease at 30 months after the presentation. Conclusions: The diagnosis of SMARCA4/BRG1-deficient NSCLC is frequently difficult because of no specific morphology and necessity of discrimination from SMARCA4/BRG1-deficient thoracic sarcoma, which is the practical reason this disease is sometimes missed. Immunohistochemistry for BRG1 should be encouraged for the pathological examination of NSCLC with any histology for the prompt and precise diagnosis of SMARCA4/BRG1-deficient NSCLC.

Gastric metastasis from ovarian cancer is exceptionally rare and generally occurs in advanced stages. A 71-year-old woman presented with a solitary gastric submucosal mass 8 years after the diagnosis of a stage IA ovarian serous adenocarcinoma. Endoscopy showed a tumor covered with normal gastric mucosa. Initially, a gastrointestinal stromal tumor was suspected, but biopsy revealed a histology of invasive micropapillary carcinoma, similar to the histological findings of the previously resected ovarian tumor. Clinicians should consider that in patients with a submucosal tumor and a history of ovarian cancer, gastric lesions may be secondary metastases from ovarian cancer.

Primary pulmonary neoplasms of the Ewing family of tumors (EFT) are extremely rare and usually occur in adolescents or young adults. Only about 40 cases of pulmonary EFT have been reported in English literature, and no cytological studies have been documented. In this report, we describe the cytopathological findings of a primary pulmonary EFT in an elderly patient. A 70-year-old man sought care because of a progressing cough and dyspnea. Chest computed tomography revealed a circumscribed mass of 6 cm in the left upper lobe. Fine needle aspiration cytology and core needle biopsy revealed uniform round cell proliferation. The predominant population consisted of cells with thickened nuclear membranes, finely dispersed chromatin, single distinct nucleoli, and indistinct cytoplasm. The other population consisted of smaller cells with darker chromatin. The cytoplasm stained positive for periodic acid–Schiff stain and was digested by diastase. Immunohistochemistry showed positivity for MIC2 (CD99), and focal positivity for neuron specific enolase, synaptophysin, and chromogranin A. Fluorescence in situ hybridization (FISH) revealed EWSR1 translocation. Although rare, pulmonary EFT cannot be disregarded, regardless of age. When two populations of uniform, round cells are observed, immunohistochemistry with MIC2 (CD99) and cytogenetic analysis by reverse transcription polymerase chain reaction or FISH should be considered. Cytological diagnosis may play an important role in the early diagnosis and treatment of pulmonary EFT.

International audience; Background The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (Lat(Y136F)) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of Lat(Y136F) knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD).Methods Lat(Y136F) knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed.Results Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment.Conclusions Lat(Y136F) knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the Lat(Y136F) knock-in mouse strain to represent a promising model for human IgG4-RD.